In stark contrast to Mendelian disorders, the majority of complex trait-associated common variants map to non-protein coding regions. Since there is a less well-developed genetic code for the much larger non- protein coding portion of the genome, identifying the gene(s) and causal alleles underlying non- Mendelian/complex traits presents a challenge. Given the rapidity with which genome wide association studies (GWAS) are discovering regions associated with complex traits, gene and causal allele identification have become severe bottlenecks. The overall goal of this proposal is to outline a coherent strategy to discover causal genes and alleles underlying complex traits. While the proposal focuses on cancer, the strategies are generic and can be applied to any non-protein coding locus. The central hypothesis is that cancer risk loci are regulatory elements. Recent data convincingly demonstrate that GWAS loci are enriched for regulatory elements. Regulatory elements can control the level of expression of genes. Causal genes and variants are difficult to discover because the scientific community is less adept at annotating the non-protein coding portion of the genome. This proposal seeks to utilize two powerful tools, circular chromosome conformation capture (4C) and genome editing to identify causal genes and alleles. The first aim will discover the causal alleles at risk loci where a target gene has already been identified. Using the target gene promoter as a bait for 4C, we will identify the genomic regions that are physically interacting with the promoter. Each of these interacting regions are candidate regulatory elements. In parallel, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) evaluation of the candidate causal variants will be performed. Information from these assays will be integrated with genetic and epigenetic data to define the causal variant. Since we know the target gene, modifications at the causal allele site will be expected to influence transcription of this gene and will provide definitive proof of causal variant identification. Aim will focus on identifying the causal gene and variant at a risk locus where a target gene has not been identified. The locus under study is a risk locus for breast, prostate, and ovarian cancers. We specifically hypothesize that this region is acting through a common mechanism for all three cancers. Again, we will employ 4C and CRISPR technologies to define the causal variant and gene. At the completion of this project, we fully anticipate that we will have begun to unravel the genes/pathways that initiate human prostate cancer. Discovering the mechanisms underlying prostate cancer will not only inform the biology of this disease, but may also reveal opportunities to more rationally intervene in treatment and prevention.